Project Summary Our collaborative basic science and clinical team will elucidate the mechanism(s) of ultrasound scattering in biological tissues by systematically studying a significant component of ultrasonic scattering, the structure function (SF), using solid tumors from animal models and hepatocellular carcinoma (HCC) in adult human subjects, and thereby improve the accuracy of Quantitative Ultrasound (QUS, the quantification of tissue microstructure) techniques in noninvasive tumor detection and classification. The SF concept arises in the context of wave scattering: the scattered power of a collection of scatterers depends not only on the properties of the individual scatterers (modeled by the form factor), but also on the spatial correlation among the scatterers (modeled by the SF). Structure function is new: The SF has largely been overlooked wherein the scatterer positions are assumed to be uncorrelated (i.e., SF is unity). The unity SF assumption is not appropriate for dense scattering media (e.g., solid tumors and most parenchymal tissues) or sparse media showing special patterns of scatterer distribution. Non-unity SF has mostly been studied on simple scattering media such as physical phantoms and blood. This investigation is new, and numerous basic science and technical innovations will be pursued. Our goal is to systematically study the SF using animal solid tumors and human liver and HCC data to improve ultrasonic scattering models and ultimately the diagnostic value of QUS outcomes. The research makes contributions at the basic science level to elucidate the scattering mechanisms by SF model development and validate using animal tumor models in vivo, and at the translational level to improve the accuracy of tumor detection/classification using human liver and HCC data. Central hypotheses and aims: 1) The SF is critical to elucidate ultrasonic scattering mechanism(s) in biological tissues. 2) The SF is sensitive to certain disease types and stages. 3) The accuracy of QUS to noninvasively detect/classify tissues/tumors in vivo will be significantly improved when the SF is utilized compared to when it is not utilized. To test these hypotheses, we have designed a research program with the following aims: Aim 1. Develop theoretical SF models that match scatterer spatial distributions of tumor/tissue types under investigation. Aim 2. Validate SF models using solid tumors in mice/rats. Aim 3. Test the diagnostic value of SF using clinical human liver data from 100 nonalcoholic fatty liver disease (NAFLD) participants, 150 cirrhotic participants, 50 HCC participants, and 150 normal participants. Summary/Impact: The SF is an ultrasound echo component that is determined by and sensitive to the architectural pattern of tissue microstructure (e.g., liver cell nuclei). The SF will be a clinically valuable imaging biomarker for disease diagnosis because many disease processes (e.g., HCC) remarkably change to a unique architectural pattern and consequently change the SF derived from the ultrasound signal.